Vibrio cholerae, a gram-negative halophilic bacterium found in aquatic environments is the causative agent of the epidemic and deadly diarrheal disease cholera. We have previously shown that ingestion of pathogenic strains of V. cholerae by Drosophila melanogaster results in lethal infection. This infection is dependent on cholera toxin expression by the bacterium as well as on the presence of wild-type levels of adenylyl cyclase, Gsa, and Ca2+-activated K+ channels in the fly. These findings support the conclusion that cholera toxin is the primary virulence factor in both human and Drosophila infection and acts by a similar mechanism in both of these organisms. Based on these results, we hypothesize that the fly may be a useful and practical model host in which to identify host factors that impact the course of V. cholerae infection. To this end, we have initiated a forward genetic screen to identify Drosophila mutants whose susceptibility ty. These experiments will lay the ground work for future studies using the fly as a model to identify novel therapeutics for cholera, modulators of the immune response to V. cholerae, and factors that influence the susceptibility of the mammalian host to V. cholerae infection. We propose to complete the following specific aims: Specific Aim 1: Completion of a genetic screen to identify host proteins that impact the susceptibility of Drosophila melanogaster to V. cholerae infection. Specific Aim 2: To establish intestinal apoptosis as a factor in the susceptibility of Drosophila to V. cholerae infection and to identify the Drosophila signaling pathways that modulate intestinal apoptosis. Specific Aim 3: To identify Vibrio cholerae factors those are responsible for stimulation of the apoptotic response. 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